The primary goal of research outlined in this proposal is the development of general, stereocontrolled annulation approaches to highly functionalized seven- and eight-membered rings. Readily accessible synthons have been designed to allow conversion to carbocycles and heterocycles bearing different substitution patterns and stereochemistries. Control of stereochemistry and regiochemistry is established by a novel mechanistic pathway which has high predictability and reliability. This permits unprecedented control in conversion of acyclic synthons to important carbocycles and heterocycles. In terms of new synthetic methods development, several areas will be explored. Procedures for fragmenting the bicyclic ether subunit initially generated in the annulation process will be investigated. Extension of the method to the synthesis of bicyclic amines will also be examined. If successful, the method would have implications in the synthesis of tropane alkaloids as well alkaloids containing five- and six-membered ring nitrogen heterocycles. Other fundamental studies are described which may lead to significant new areas for study. A natural evolution of this program is the application of these new synthetic methods to the synthesis of complex organic molecules. Challenging target structures have been put forward which will be constructed in order to demonstrate the value of these synthetic methods. Included are approaches to the eunicellin/cladiellin/asbestinin class of diterpenes, which possess particular importance in health related fields. It is suggested that the eunicellin ring system may be accessed by the annulation strategy outlined in this proposal, leading to a synthesis of sclerophytin B. Finally, an approach to the "in-out" bridged bicyclic skeleton of ingenol pharmacophores is proposed.